1. Field of the Invention
This invention relates to a method for preparing 7.alpha.-acylthio-4-en-3-oxosteroids. More particularly, it relates to a commercial method for preparing a 7.alpha.-acylthio-4-en-3-oxosteroid (hereinafter referred to as "7.alpha.-acylthio derivative") such as 7.alpha.-acetylthio-17-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone (hereinafter referred to as "spironolactone") which is an antialdosteronic diuretic extremely effective in therapy.
In one embodiment, this invention relates to a method for converting 7.beta.-acetylthio-17-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone (hereinafter referred to as "7.beta.-acetylthio derivative") which is therapeutically inactive into the spironolactone, that is, its 7.alpha.-acetylthio derivative, extremely effective in therapy in a high yield.
2. Description of the Prior Art
It is known that spironolactone is usually prepared by reacting 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone with a large excess of thioacetic acid under heating [J. Org. Chem., 27, 3325(1962)]. According to such method, however, the 7.beta.-acetylthio derivative which is therapeutically inactive is formed as a by-product in a proportion of about 25%.
Accordingly, in order to obtain spironolactone from 17-hydroxy-3-oxo- 17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone in a high yield it is necessary to convert the undesirable 7.beta.-acetylthio derivative into the spironolactone by some means.
In a conventional procedure, the reaction mixture of the above-mentioned addition reaction is worked up by a suitable purification technique such as crystallization to isolate the spironolactone of high purity. As a result, the filtrate or mother liquor contains a relatively large amount of spironolactone together with the 7.beta.-acetylthio derivative by-product.
The 7.beta.-acetylthio derivative can be converted into the spironolactone by treating the 7.beta.-acetylthio derivative with a base such as sodium hydroxide or sodium methoxide to give the starting material, 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone, followed by the addition reaction with thioacetic acid. (This method is hereinafter referred to as "elimination-addition method".)
However, it has been found in our experiments that the elimination-addition method suffers from several disadvantages . First, the intermediate 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone cannot be obtained in an yield exceeding 90% and appreciable amounts of by-products are formed. Accordingly, the 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone obtained in this way does not have enough purity to use it as the starting material for the thioacetic acid addition reaction which is intended to provide the spironolactone of high purity, and usually it must be purified prior to use, which results in a further decrease in the actual yield.
Secondly, the method is disadvantageous in that the relatively large amount of spironolactone usually accompanying the crude 7.beta.-acetylthioderivative is also returned to the starting material, 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone during the base treatment involved in the method.
Thirdly, since both the 7.beta.-acetylthio derivative and spironolactone are returned to the starting material, 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone, the addition reaction of thioacetic acid must be conducted again to give the desired spironolactone. During such reaction, as previously mentioned, the therapeutically inactive 7.beta.-acetylthio derivative is formed again as by-product and hence the overall yield of the spironolactone is relatively low.
Finally, it is evident from the above that the elimination addition method is highly disadvantageous as a commercial method since it requires a large number of steps and complicated procedures.